Changes in white matter have been reported in depression, schizophrenia, and post- traumatic stress disorder (PTSD) and suicide, suggesting that altered myelination may be a new mechanism by which psychopathologies emerge. We found that stress and the adrenal stress hormones, glucocorticoids (GC), induce Neural Precursor Cells in the adult hippocampus to an oligodendrogenic fate, thereby increasing myelin production capacity. We have also demonstrated increased myelination capacity in the hippocampus of pups subjected to adverse parental care. Here, we hypothesize that early adverse experiences increase myelination across the lifespan, altering development of the brain environment and increasing susceptibility to mental illness including PTSD and depression. We propose to examine the effects that neonatal stress and adverse parental care have on long-lasting changes on white matter patterning across the lifespan, using an integrated approach that correlates molecular/cellular analysis with behavioral outputs.
In specific aims 1 -2, we will document, at the cellular level, changes in myelination and oligodendrogenesis after early life maternal separation or low maternal care, and analyze the underpinnings of myelination at the molecular level by qPCR of the transcription factors involved in cell fate choice, and myelin-related genes. Furthermore, we will correlate developmental white matter patterning with vulnerability to PTSD in response to acute stress in adulthood.
In specific aim 3, we will use anti-GC gene intervention vectors to try to prevent misdevelopment of the white matter when delivered in early life, or mitigate persistent white matter dysregulation when delivered in adulthood.
In specific aim 4, we will expand these cellular-level analyses to the behavioral level by testing for depression/anxiety behavior and hippocampus-dependent cognitive performance in each experimental group. Together, these aims will give us a comprehensive picture of the development of altered white matter patterning after early adverse experience, ranging from quantification of myelin and oligodendrogenesis at different developmental time points to ultimate effects in impaired behavior and cognitive function. This application is innovative in (1) focusing on white matter support cells, rather than neurons, as a developmental basis for mental illness and (2) using interdisciplinary, integrative approaches to explore the developmental basis of mental illness. This project aims to examine whether adverse early experiences exert long-lasting changes on oligodendrogenesis and myelination across the lifespan, and render vulnerability to development of mental illness such as post-traumatic stress disorder and depression. Anti-glucocorticoids genetic therapies are employed as tools to prevent or reverse these effects. This application is innovative, as it sheds light on a generally unexplored issue-the persistent dysregulation of white matter by early adverse experience, and how this contributes to the development of brain malfunction in adulthood, specifically in the context of mental illness.

Public Health Relevance

This project aims to examine whether adverse early experiences exert long-lasting changes on oligodendrogenesis and myelination across the lifespan, and render vulnerability to development of mental illness such as post-traumatic stress disorder and depression. Anti-glucocorticoid genetic therapies are employed as tools to prevent or reverse these effects. This proposal is innovative, as it sheds light on a generally unexplored issue-the persistent dysregulation of white matter by early adverse experience, and how this contributes to the development of brain malfunction in adulthood, specifically in the context of mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087495-05
Application #
8464790
Study Section
Special Emphasis Panel (ZMH1-ERB-L (06))
Program Officer
Panchision, David M
Project Start
2009-09-30
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$411,553
Indirect Cost
$137,639
Name
University of California Berkeley
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Chetty, S; Friedman, A R; Taravosh-Lahn, K et al. (2014) Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus. Mol Psychiatry 19:1275-83
Kirby, E D; Friedman, A R; Covarrubias, D et al. (2012) Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons. Mol Psychiatry 17:527-36